Exp Mol Med. 2025 Mar 3. doi: 10.1038/s12276-025-01418-z. Online ahead of print.

ABSTRACT

The trapping of pathogenic ligands can potentially be used to prevent signal transduction mediated by catabolic factor expression in osteoarthritis (OA). Although vaspin is known to function as a pathogenic ligand and represents a novel adipokine, little is known about its function and the impact of its nebulization-based administration in OA. Here we provide a report on the function of vaspin in articular chondrocytes and OA model mice. RNA sequencing analysis and ingenuity pathway analysis demonstrated that vaspin upregulation in chondrocytes triggers OA development-related signaling. Vaspin is upregulated in the injured cartilage of patients with OA and DMM (Destabilization of the Medial Meniscus) mice, and its overexpression induces catabolic factor expression in vitro under OA-mimicked conditions. Col2a1-vaspin Tg (Transgenic) animals showed extensive cartilage degradation, whereas vaspin-/- (knockout) mice exhibited decreased OA development. Furthermore, in silico and biochemical analyses showed that vaspin activates the p38 and JNK signaling pathways to regulate AP-1-driven catabolic factor production and cartilage breakdown. Finally, we identified and characterized a vaspin-targeting nanobody, vas nanobody, and showed that intraarticularly injected vas nanobody could effectively block the vaspin-AP-1 axis to treat OA in DMM mice. Together, our results suggest that blockade of the vaspin-AP-1 axis could be an effective therapeutic approach for preventing OA development.

PMID:40025171 | DOI:10.1038/s12276-025-01418-z

Sci Rep. 2025 Mar 1;15(1):7314. doi: 10.1038/s41598-025-91546-3.

ABSTRACT

Lamin B1 (LMNB1) is an intermediate filament protein that is an integral component of the nuclear lamina, a structure that is critical for nuclear organization and function. Mutations involving the lamin B1 gene cause the adult-onset demyelinating disorder, Autosomal Dominant Leukodystrophy (ADLD) which is charactered by increased lamin B1 expression. Increased LMNB1 expression is also associated with poorer outcomes in multiple cancer subtypes. Reducing LMNB1 is thus an attractive therapeutic pathway for ADLD and potentially other diseases. Here we present the results of a high throughput / high content screen (HTS/HCS) to identify small molecules that reduce LMNB1 levels. Approximately 97,000 molecules were screened using an inducible mouse fibroblast model of LMNB1 overexpression that we have previously generated. Two small molecules, Pubchem CID 662896 and CID 5308648, were identified that reduced LMNB1 in a dose dependent manner without causing cellular toxicity and corrected nuclear abnormalities associated with LMNB1 overexpression, a hallmark of ADLD. CID 662896 also reduced LMNB1 levels in ADLD patient fibroblast samples, exhibited favorable "drug-like" physicochemical properties and crossed the blood brain barrier in mouse studies. While CID 662896 may be a promising candidate for ADLD therapy, further investigations are required to determine its mechanism of action and ability to target disease relevant cell types.

PMID:40025114 | DOI:10.1038/s41598-025-91546-3

Sci Rep. 2025 Mar 1;15(1):7283. doi: 10.1038/s41598-025-89684-9.

ABSTRACT

Marine copepod communities play crucial roles in ocean ecosystems. However, their accurate assessment remains challenging due to taxonomic complexities. This study combines morphological and DNA metabarcoding approaches to evaluate copepod diversity and community structure in the northern East China Sea. Zooplankton samples were collected from 10 stations along a coastal-offshore gradient in August 2019. Morphological analysis identified 34 species from 25 genera, while DNA metabarcoding detected 31 species from 20 genera. Both methods revealed distinct coastal and offshore assemblages, with Paracalanus parvus s.l. as the dominant species across all stations. A significant positive correlation was found between morphology-based individual counts and metabarcoding sequence reads (Spearman's Rho = 0.58, p < 0.001), improving at the genus level (Rho = 0.70, p < 0.001). Redundancy analysis revealed that salinity, temperature, and phytoplankton density significantly influenced copepod distribution. Although both approaches captured similar broad-scale patterns, they provided complementary insights into community structure. Morphological identification was more effective for detecting Cyclopoida diversity, whereas DNA metabarcoding had greater sensitivity for specific Calanoid species. This study underscores the value of integrating traditional and molecular methods for marine biodiversity assessment, especially in the context of global environmental changes.

PMID:40025088 | DOI:10.1038/s41598-025-89684-9

Biotechnol Adv. 2025 Feb 28:108544. doi: 10.1016/j.biotechadv.2025.108544. Online ahead of print.

ABSTRACT

The persistent demand for plastic commodities, inadequate recycling infrastructure, and pervasive environmental contamination due to plastic waste present a formidable global challenge. Recycling, degradation and upcycling are the three most important ways to solve the problem of plastic pollution. Sequential enzymatic and microbial degradation of mechanically and chemically pre-treated plastic waste can be orchestrated, followed by microbial conversion into value-added chemicals and polymers through mixed culture systems. Furthermore, plastics-degrading enzymes can be optimized through protein engineering to enhance their specific binding capacities, stability, and catalytic efficiency across a broad spectrum of polymer substrates under challenging high salinity and temperature conditions. Also, the production and formulation of enzyme mixtures can be fine-tuned to suit specific waste compositions, facilitating their effective deployment both in vitro, in vivo and in combination with chemical technologies. Here, we emphasized the comprehensive strategy leveraging microbial processes to transform mixed plastics of fossil-derived polymers such as PP, PE, PU, PET, and PS, most notably polyesters, in conjunction with potential biodegradable alternatives such as PLA and PHA. Any residual material resistant to enzymatic degradation can be reintroduced into the process loop following appropriate physicochemical treatment.

PMID:40024585 | DOI:10.1016/j.biotechadv.2025.108544

Lab Invest. 2025 Feb 28:104123. doi: 10.1016/j.labinv.2025.104123. Online ahead of print.

ABSTRACT

Preferentially Expressed Antigen in Melanoma (PRAME) and Ten-Eleven Translocation (TET) dioxygenase-mediated 5-hydroxymethylcytosine (5hmC) are emerging melanoma biomarkers. We observed an inverse correlation between PRAME expression and 5hmC levels in benign nevi, melanoma in situ, primary invasive melanoma, and metastatic melanomas via immunohistochemistry and multiplex immunofluorescence: nevi exhibited high 5hmC and low PRAME, whereas melanomas showed the opposite pattern. Single-cell multiplex imaging of melanoma precursors revealed that diminished 5hmC coincides with PRAME upregulation in premalignant cells. Analysis of TCGA and GTEx databases confirmed a negative relationship between TET2 and PRAME mRNA expression in melanoma. Additionally, 5hmC levels were reduced at the PRAME 5' promoter in melanoma compared to nevi, suggesting a role for 5hmC in PRAME transcription. Restoring 5hmC levels via TET2 overexpression notably reduced PRAME expression in melanoma cell lines. These findings establish a function of TET2-mediated DNA hydroxymethylation in regulating PRAME expression and demonstrate epigenetic reprogramming as pivotal in melanoma tumorigenesis.

PMID:40024557 | DOI:10.1016/j.labinv.2025.104123

J Mol Biol. 2025 Feb 28:169054. doi: 10.1016/j.jmb.2025.169054. Online ahead of print.

ABSTRACT

I am a Professor of Biochemistry, Biophysics and Structural Biology and Plant and Microbial Biology at the University of California in Berkeley. I was born and raised in India, emigrated to the United States to attend university, earning a B.S. in Molecular Biology and a Ph.D. in Biochemistry at the University of Wisconsin in Madison. Following post-doctoral studies with Lawrence Bogorad at Harvard University where I became interested in genetic control of trace element quotas, I joined the department of Chemistry and Biochemistry at UCLA. One of the first to appreciate essential trace metals as potential regulators of gene expression, I articulated the details of the nutritional Cu regulon in Chlamydomonas. In parallel, I used genetic approaches to discover the genes governing missing steps in tetrapyrrole metabolism, including the attachment of heme to apocytochromes in the thylakoid lumen and the factors catalyzing the formation of ring V in chlorophyll. After biochemistry and classical genetics, I embraced genomics, taking a leadership role on the Joint Genome Institute's efforts on the Chlamydomonas genome and more recently, contributing to high quality assemblies of several genomes in the green algal radiation and large transcriptomic and proteomic datasets - focusing on the diel metabolic cycle in synchronized cultures and acclimation to key environmental and nutritional stressors -- that are well-used and appreciated by the community. A new venture in Berkeley is the promotion of Auxenochlorella protothecoides as the true "green yeast" and as a platform for engineering algae to produce useful bioproducts.

PMID:40024437 | DOI:10.1016/j.jmb.2025.169054

Biochem Pharmacol. 2025 Feb 28:116839. doi: 10.1016/j.bcp.2025.116839. Online ahead of print.

ABSTRACT

Dengue viruses (DENV) pose significant health threats, with no approved antiviral drugs currently available, creating an urgent need for new therapies. This study screened FDA-approved drugs for their antiviral ability against DENV and identified three promising candidates: darunavir (DRV), domperidone, and tetracycline. DRV demonstrated the highest efficacy against three DENV serotypes, with half-maximal effective concentrations (EC50) below 1 µM, surpassing the performance of tetracycline and domperidone. It effectively blocked DENV envelope (E) protein attachment to two type cells with EC50 values less than 0.2 μM. Domperidone reduced DENV-2 attachment to TE671 cells (EC50 = 3.08 μM) but was less effective in BHK-21 cells, while tetracycline inhibited NS3 protease (IC50 = 1.12 μM). Among DRV's structurally related drugs, fosamprenavir (FPV) significantly reduced DENV infectivity and virus yield, with EC50 values below 0.5 µM. In vivo, DRV at 1, 2, and 5 mg/kg achieved 100 % survival in suckling mice, compared to 83.5 % with FPV. Real-time RT-PCR showed DRV more effectively reduced DENV-2 RNA in mouse brains than FPV. Molecular docking showed DRV and FPV bind tightly to the DENV-2 E protein's N-octyl-β-D-glucoside (βOG) hydrophobic pocket, with DRV forming stronger interactions than FPV. Chimeric DENV-2 single-round infectious particle tests confirmed DRV's effective targeting of this pocket, though mutations at K128, L198, Q200, I270, and T280 reduced its efficacy. These findings highlight DRV as a potent antiviral agent against DENV, targeting the E protein's βOG hydrophobic pocket, with the potential for rapid deployment in treating and preventing infections.

PMID:40024350 | DOI:10.1016/j.bcp.2025.116839

Vaccine. 2025 Mar 1;53:126948. doi: 10.1016/j.vaccine.2025.126948. Online ahead of print.

ABSTRACT

In England, and many other countries, immunity to SARS-CoV-2 infection and COVID-19 disease is highly heterogeneous. Immunity has been acquired through natural infection, primary and booster vaccination, while protection has been lost through waning immunity and viral mutation. During the height of the pandemic in England, the main aim was to rapidly protect the population and large supplies of vaccine were pre-purchased, eliminating the need for cost-effective calculations. As we move to an era where for the majority of the population SARS-CoV-2 infections cause relatively mild disease, and vaccine stocks need to be re-purchased, it is important we consider the cost-effectiveness and economic value of COVID-19 vaccination programmes. Here using data from 2023 and 2024 in England on COVID-19 hospital admissions, ICU admissions and deaths, coupled with bespoke health economic costs, we consider the willingness to pay threshold for COVID-19 vaccines in different age and risk groups. Willingness to pay thresholds vary from less than £1 for younger age-groups without any risk factors, to over £100 for older age-groups with comorbidities that place them at risk. This extreme non-linear dependence on age, means that despite the different method of estimating vaccine effectiveness, there is considerable qualitative agreement on the willingness to pay threshold, and therefore which ages it is cost-effective to vaccinate. The historic offer of COVID-19 vaccination to those 65 and over for the autumn 2023 programme and those over 75 for the spring 2023 programme, aligns with our cost- effective threshold for pre-purchased vaccine when the only cost was administration. However, for future programmes, when vaccine costs are included, the age-thresholds slowly increase thereby demonstrating the continued importance of protecting the eldest and most vulnerable in the population.

PMID:40023905 | DOI:10.1016/j.vaccine.2025.126948

Drug Saf. 2025 Mar 1. doi: 10.1007/s40264-025-01536-7. Online ahead of print.

ABSTRACT

BACKGROUND: The Pharmacovigilance Risk Assessment Committee (PRAC) plays a central role in the European Union's pharmacovigilance system, evaluating drug safety through several procedures and activities. Despite its central role, few studies have quantitatively investigated the PRAC's activities from a system's perspective.

OBJECTIVE: This study aims to map PRAC's evaluation of safety signals and concerns using antidiabetic products as a case. It characterises the drugs and adverse events involved, analyses the PRAC-led regulatory procedures where the safety signals and concerns were evaluated, and provides a comprehensive review of PRAC meeting minutes.

METHODS: From PRAC meeting minutes, we retrieved information on all antidiabetic drug-related adverse events discussed from 2012 to 2022. We identified drug-adverse event evaluations based on the discussion content. These were described by drug classes, System Organ Classes, PRAC procedures, and the evaluation outcomes corresponding to recommendations for regulatory actions. We also analysed the sequence of PRAC-led procedures and activities addressing drug-adverse event pairs across meeting minutes.

RESULTS: A total of 321 drug-adverse event pairs were identified, with 14 pairs associated with drug classes. Second-generation antidiabetic agents, including sodium-glucose transport protein-2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase 4 inhibitors, were the most frequently discussed. Of these, 62 pairs underwent multiple evaluations, resulting in a total of 413 evaluations. In 48% of evaluations, no regulatory action was required. Most evaluations (97%) were concluded in a single procedure, and 66% were concluded in one meeting. Periodic safety update reports accounted for 54% of drug-adverse event evaluations and updates to product information were the most frequent outcome. Signal assessment and prioritisation procedures, while less common, resulted in more diverse recommendations for regulatory action. Referrals were infrequent (N = 5) and were often triggered by the signal assessment and prioritisation procedure.

CONCLUSIONS: Periodic safety update reports are the primary source for PRAC evaluations of safety signals although they are not intended for notification of new urgent safety information. Compared with periodic safety update reports, the signal assessment and prioritisation procedure evaluates fewer signals but leads to a wider range of regulatory actions, from risk minimisation measures to referrals. This difference may be attributed to the fact that signals detected in periodic safety update reports are not intended for urgent safety issues, these should be assessed through the signal assessment and prioritisation procedure, as the latter involves real-time signal management, whereas the periodic safety update reports are conducted at predefined intervals.

PMID:40024970 | DOI:10.1007/s40264-025-01536-7

Wiad Lek. 2024;78(1):187-196. doi: 10.36740/WLek/197143.

ABSTRACT

OBJECTIVE: Aim: To investigate how and why antidepressant side effects occur, in order to use them effectively in clinical practice.

PATIENTS AND METHODS: Materials and Methods: We have studied modern literary sources on the topic of side effects of antidepressant and presented in the form of a literature review in this article. Electronic Scopus and Pubmed databases were searched for articles on the studied topic. The review included original articles, research, and official recommendations from medical associations.

CONCLUSION: Conclusions: Side effects of antidepressants can reduce treatment adherence and delay recovery. Therefore, it is extremely important to consider possible side effects when choosing a therapy. While there is no perfect antidepressant that works quickly and is completely free of side effects, newer antidepressants are safer, better tolerated, and associated with lower rates of treatment failure. Most side effects occur as a consequence of the basic mechanism of action of the drugs. Therefore, it is important to understand the neurobiology of side effects, their frequency and risks, ways to prevent them or use them to your advantage resources.

PMID:40023872 | DOI:10.36740/WLek/197143

Rev Mal Respir. 2025 Mar;42(3):148-152. doi: 10.1016/j.rmr.2025.02.009. Epub 2025 Feb 28.

ABSTRACT

Post-infectious bronchiolitis obliterans (PIBO) is a rare but severe pulmonary disease in children, often associated with adenovirus infection. Risk factors include male sex, hypoxemia, and mechanical ventilation. Diagnosis is based on clinical history, bronchial obstruction, and radiological abnormalities. PIBO is characterized by chronic inflammation leading to tissue remodeling and bronchiolar fibrosis. Airway epithelial lesions, potentially linked to viral infection, are considered key mechanisms of PIBO. In the absence of specific treatments, research efforts aim to better understand mechanisms of PIBO, identify biomarkers, and improve management strategies.

PMID:40023714 | DOI:10.1016/j.rmr.2025.02.009

Int J Gynecol Cancer. 2025 Mar;35(3):101669. doi: 10.1016/j.ijgc.2025.101669. Epub 2025 Jan 29.

ABSTRACT

More than half of all gynecological cancers are classified as rare (annual incidence <6 per 100,000), and present significant challenges in diagnosis, management, and research. Rare cancers collectively comprise more than 20% of new cancer diagnoses and exceed the burden of individual common cancers. Their rarity complicates evidence-based guideline development, clinical trial design, and drug access, and is exacerbated by variations in epidemiology, histology, and biological behavior. Key controversies include the need for centralized pathological reviews and harmonized diagnostic criteria. Recent World Health Organization classification updates, such as the redefinition of ovarian and fallopian tube cancers, illustrate the impact of evolving guidelines on epidemiology and patient management. Variations in the classification among pathologists and limited access to molecular diagnostics further hinder effective management. Multidisciplinary care in expert centers improves outcomes; however, significant geographic and resource disparities persist. National and international collaborations including European Reference Network for rare adult solid tumors, Gynecologic Cancer Intergroup, Gynecologic Oncology Group, Asia-Pacific Gynecologic Oncology Trials Group, and European Network for Gynaecological Oncology Trials have made strides in standardizing care and advancing research. Novel trial designs, such as basket and umbrella trials, alongside synthetic control arms, are essential for addressing the small sample sizes typical of rare tumors. Emerging consortia, such as International Ovarian Tumor Tissue Analysis Consortium and International Consortium for Low-grade Serous Ovarian Cancer, provide robust platforms for translational research and biomarker validation. However, challenges remain in fostering cross-border collaboration, streamlining regulatory pathways, and ensuring equitable access to trials and therapy. To optimize outcomes, a comprehensive approach that integrates centralized care, innovative trial designs, and international networks is imperative. This paradigm fosters the harmonization of care, accelerates translational research, and bridges the gap between scientific innovation and patient benefits.

PMID:40022843 | DOI:10.1016/j.ijgc.2025.101669

J Pharmacol Exp Ther. 2025 Feb;392(2):100057. doi: 10.1016/j.jpet.2024.100057. Epub 2024 Dec 9.

ABSTRACT

Cisplatin causes permanent hearing loss or cisplatin-induced ototoxicity in over 50% of treated patients with cancer, leading to significant social and functional limitations. Interindividual variability in developing hearing loss suggests the role of genetic predispositions to cisplatin-induced hearing loss. We investigated genetic associations between cisplatin-induced ototoxicity and toll-like receptor 4 (TLR4), an immune receptor known to mediate inflammatory responses to cisplatin. Using a case-control candidate gene approach, we identified 20 single nucleotide polymorphisms at the TLR4 locus with significant protection against ototoxicity in a cohort of 213 adult patients, followed by an independent pediatric patient cohort (n = 357). Combined cohort analysis demonstrated a significant association between cisplatin-induced ototoxicity protection and a single variant in the TLR4 promoter, rs10759932. We showed that rs10759932 downregulated TLR4 expression that is normally induced by cisplatin. This work provides pharmacogenetic and functional evidence to implicate TLR4 with cisplatin-induced hearing loss in patients. SIGNIFICANCE STATEMENT: Adult and pediatric patients carrying toll-like receptor 4 (TLR4) genetic variants were protected against developing cisplatin-induced hearing loss following cisplatin treatment. Important variants in the TLR4 promoter disrupted a drug-gene interaction between cisplatin and TLR4, mirroring the protective effect conferred by genetic inhibition of TLR4. These variants have the potential to improve the prediction of cisplatin toxicity, allowing for more precise chemotherapy treatment.

PMID:40023593 | DOI:10.1016/j.jpet.2024.100057

J Cyst Fibros. 2025 Feb 28:S1569-1993(25)00068-2. doi: 10.1016/j.jcf.2025.02.018. Online ahead of print.

NO ABSTRACT

PMID:40023749 | DOI:10.1016/j.jcf.2025.02.018

Rev Mal Respir. 2025 Feb 28:S0761-8425(25)00047-6. doi: 10.1016/j.rmr.2025.02.004. Online ahead of print.

ABSTRACT

Cystic fibrosis is a genetic disease in which phenotypic variability is still poorly understood. Our hypothesis is that the exposome, and more specifically exposure to air pollution and/or anxiety, could play a role in this phenomenon. In this context, we have developed an experimental study in which cystic fibrosis mice were exposed to stress (anxiety) and then to complex realistic atmospheres. Our results should provide mechanistic elements for a better understanding of the phenotypic variability observed in cystic fibrosis patients and thus be able to propose new avenues for better management of these patients.

PMID:40023717 | DOI:10.1016/j.rmr.2025.02.004

Rev Mal Respir. 2025 Feb 28:S0761-8425(25)00050-6. doi: 10.1016/j.rmr.2025.02.007. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a rare, progressive and fatal disease without pharmacologic curative treatments for the patients. TGF-β is a crucial cytokine in the fibrotic process, and its intracellular signaling pathways are complex and rely on the activation of its receptor. This review summarizes our knowledge on the regulatory checkpoints of the TGF-β signaling. In addition, the main strategies and key potential therapeutic targets identified over recent years are presented, with particular emphasis laid on how they can be used to develop new treatments for pulmonary fibrosis.

PMID:40023715 | DOI:10.1016/j.rmr.2025.02.007

Bioresour Technol. 2025 Feb 27:132313. doi: 10.1016/j.biortech.2025.132313. Online ahead of print.

ABSTRACT

Lignocellulose is the most abundant terrestrial biomass type, and lignocellulose hydrolysate has the potential to replace glucose for microbial fermentation. Halomonas bluephagenesis has significant advantages in producing bioplastics polyhydroxyalkanoates (PHA), but there is relatively little research on the use of lignocellulose hydrolysate for this strain. In present study, H. bluephagenesis was engineered to use xylose and lignocellulose hydrolysate to produce PHB. Firstly, four xylose metabolism pathways were established. Secondly, several xfp genes were compared and genes in pathway I (xylA and xfp gene) were integrated into the genome. Thirdly, H. bluephagenesis was found to be able to utilize glucose and xylose simultaneously. H. bluephagenesis T39 containing xylA and xfp generated 15 g/L CDW containing 76 wt% PHB when cultured in lignocellulose hydrolysate, and it was grown to 62 g/L CDW containing 67 wt% PHB in a 7 L bioreactor. H. bluephagenesis T43 harboring xylA was found able to synthesize P(3HB-4HB-3HV) containing 3-hydroxybutyrate (3HB), 4-hydroxybutyrte (4HB) and 3-hydroxyvalerate (3HV) when grown on lignocellulose hydrolysate.

PMID:40023329 | DOI:10.1016/j.biortech.2025.132313

Brain Behav Immun. 2025 Feb 27:S0889-1591(25)00070-4. doi: 10.1016/j.bbi.2025.02.030. Online ahead of print.

ABSTRACT

Autism Spectrum Disorder (ASD) is a highly prevalent neurodevelopmental condition characterized by social communication deficits and repetitive/restricted behaviors. Several studies showed that oxidative stress and inflammation may contribute to ASD. Indeed, increased levels of oxygen radicals and pro-inflammatory molecules were described in the brain and peripheral blood of persons with ASD and mouse models. Despite this, a potential direct connection between oxidative stress and inflammation within specific brain areas and ASD-related behaviors has not been investigated in detail yet. Here, we used RT-qPCR, RNA sequencing, metabolomics, immunohistochemistry, and flow cytometry to show that pro-inflammatory molecules were increased in the cerebellum and periphery of mice lacking Cntnap2, a robust model of ASD. In parallel, oxidative stress was present in the cerebellum of mutant animals. Systemic treatment with N-acetyl-cysteine (NAC) rescued cerebellar oxidative stress, inflammation, as well as motor and social impairments in Cntnap2-/- mice, concomitant with enhanced function of microglia cells in NAC-treated mutants. Intriguingly, social deficits, cerebellar inflammation, and microglia dysfunction were induced by NAC in Cntnap2+/+ animals. Our findings suggest that the interplay between oxidative stress and inflammation accompanied by genetic vulnerability may underlie ASD-related behaviors in Cntnap2 mutant mice.

PMID:40023202 | DOI:10.1016/j.bbi.2025.02.030

Cell Syst. 2025 Feb 21:101202. doi: 10.1016/j.cels.2025.101202. Online ahead of print.

ABSTRACT

Regions on a host protein that interact with virus proteins (exogenous interfaces) frequently overlap with those that interact with other host proteins (endogenous interfaces), resulting in competition between hosts and viruses for these shared interfaces (mimic-targeted interfaces). Yet, the evolutionary consequences of this competitive relationship on the host are not well understood. Here, we integrate experimentally determined structures and homology-based templates of protein complexes with protein-protein interaction networks to construct a high-resolution human-virus structural interaction network. We perform site-specific evolutionary rate analyses on this structural interaction network and find that exogenous-specific interfaces evolve faster than endogenous-specific interfaces. Mimic-targeted interfaces evolve as fast as exogenous-specific interfaces, despite being targeted by both human and virus proteins. Our findings suggest that virus targeting plays a dominant role in host interfacial evolution within the context of domain-domain interactions and that mimic-targeted interfaces on human proteins are the key battleground for a mammalian-specific host-virus evolutionary arms race.

PMID:40023148 | DOI:10.1016/j.cels.2025.101202

Tissue Cell. 2025 Feb 28;94:102806. doi: 10.1016/j.tice.2025.102806. Online ahead of print.

ABSTRACT

BACKGROUND: Neurons, distributed throughout the body, regulate various bodily functions. The recovery of the nervous system is often slow and can be irreversible. Currently, the approach of using mesenchymal stem cells (MSCs) in conjunction with conventional treatments for nervous system injuries is being explored. Nanoemulsions are systems designed for the nanoscale delivery of drug cargoes. Foeniculum vulgare (F. vulgare), a medicinal plant long utilized in complementary medicine, is the focus of this study. The aim is to utilize nanoemulsions of fennel to induce the differentiation of MSCs into neural-like cells in vitro.

MATERIALS AND METHODS: Human adipose-derived mesenchymal stem cells (hADSCs) were commercially purchased. These cells were cultured in DMEM medium containing 10 % fetal bovine serum and 1 % penicillin-streptomycin antibiotic. Based on a sequential extraction method, n-hexane (Hex), ethyl acetate (EtAc), and ethanolic extracts were obtained from the seeds of F. vulgare. To prepare the F. vulgare extract nanoemulsion, the aqueous phase (distilled water), the oily part (F. vulgare extract), Span 80 and Tween 20 were used. The optimal dose of F. vulgare nanoemulsion was determined using the MTT assay and acridine orange/ethidium bromide (AO/EB) staining. Neural differentiation was induced using a specialized differentiation medium on the MSCs, with the prepared nanoemulsions acting as inducers. The neural differentiation of the human differentiated hADSCs was studied and evaluated through Real-time PCR and immunocytochemistry (ICC) techniques on days 7 and 14.

RESULTS: The results obtained from the MTT and AO/EB tests indicated that the optimal dose of F. vulgare nanoemulsions is 1 μg/ml. Analysis of neural differentiation index gene expression revealed a significant (P ≤ 0.05) upregulation of MAP-2, β-tubulin III, and NSE genes on days 7 and 14 following treatment with the nanoemulsions. It is noteworthy that the nanoemulsion prepared from the hexane extract of the plant showed a significant increase in the expression of marker genes in the process of neural differentiation. Protein expression analysis demonstrated an increase in MAP-2, β-tubulin III, and NSE (gamma enolase) proteins in response to the nanoemulsion inducers compared to the control group (TCPS).

DISCUSSION: Overall, our findings indicate that F. vulgare nanoemulsions have a positive effect on the expression of genes and proteins related to neural differentiation in hADSCs. The proposed protocol may serve as a potential therapeutic strategy in complementary medicine for patients seeking to improve injuries to the nervous system. However, further studies and performance measurements are necessary in future research to confirm these results.

PMID:40022910 | DOI:10.1016/j.tice.2025.102806